Skip to main content
SpringerLink
Log in

The Ionizing Radiation-Induced Bystander Effect: Evidence, Mechanism, and Significance

  • Chapter
  • First Online:
Pathobiology of Cancer Regimen-Related Toxicities

Abstract

It has long been considered that the important biological effects of ­ionizing radiation are a direct consequence of unrepaired or misrepaired DNA damage occurring in the irradiated cells. It was presumed that no effect would occur in cells in the population that receive no direct radiation exposure. However, in vitro evidence generated over the past two decades has indicated that non-targeted cells in irradiated cell cultures also experience significant biochemical and phenotypic changes that are often similar to those observed in the targeted cells. Further, non-targeted tissues in partial body-irradiated rodents also experienced stressful effects, including oxidative and oncogenic effects. This phenomenon, termed the “bystander response,” has been postulated to impact both the estimation of health risks of exposure to low doses/low fluences of ionizing radiation and the induction of second primary cancers following radiotherapy. Several mechanisms involving secreted soluble factors, oxidative metabolism, gap-junction intercellular communication, and DNA repair, have been proposed to regulate radiation-induced bystander effects. The latter mechanisms are major mediators of the system responses to ionizing radiation exposure, and our knowledge of the biochemical and molecular events involved in these processes is reviewed in this chapter.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hall EJ, Giaccia AJ. Radiobiology for the radiologist. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006.

    Google Scholar 

  2. Spitz DR, Azzam EI, Li JJ, Gius D. Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: a unifying concept in stress response biology. Cancer Metastasis Rev. 2004;23:311–22.

    Article  PubMed  CAS  Google Scholar 

  3. Hayashi T, Kusunoki Y, Hakoda M, Morishita Y, Kubo Y, Maki M, et al. Radiation dose-dependent increases in inflammatory response markers in A-bomb survivors. Int J Radiat Biol. 2003;79:129–36.

    PubMed  CAS  Google Scholar 

  4. Neriishi K, Nakashima E, Delongchamp RR. Persistent subclinical inflammation among A-bomb survivors. Int J Radiat Biol. 2001;77:475–82.

    Article  PubMed  CAS  Google Scholar 

  5. Petkau A. Role of superoxide dismutase in modification of radiation injury. Br J Cancer Suppl. 1987;8:87–95.

    PubMed  CAS  Google Scholar 

  6. Kryston TB, Georgiev AB, Pissis P, Georgakilas AG. Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res. 2011;711:193–201.

    Article  PubMed  CAS  Google Scholar 

  7. Tamminga J, Kovalchuk O. Role of DNA damage and epigenetic DNA methylation changes in radiation-induced genomic instability and bystander effects in germline in vivo. Curr Mol Pharmacol. 2011;4:115–25.

    PubMed  CAS  Google Scholar 

  8. Limoli CL, Giedzinski E, Morgan WF, Swarts SG, Jones GD, Hyun W. Persistent oxidative stress in chromosomally unstable cells. Cancer Res. 2003;63:3107–11.

    PubMed  CAS  Google Scholar 

  9. Limoli CL, Hartmann A, Shephard L, Yang C, Boothman DA, Bartholomew J, et al. Apoptosis, reproductive failure, and oxidative stress in Chinese hamster ovary cells with compromised genomic integrity. Cancer Res. 1998;58:3712–8.

    PubMed  CAS  Google Scholar 

  10. Azzam EI, de Toledo SM, Little JB. Oxidative metabolism, gap junctions and the ionizing radiation-induced bystander effect. Oncogene. 2003;22:7050–7.

    Article  PubMed  CAS  Google Scholar 

  11. Hei TK, Zhou H, Chai Y, Ponnaiya B, Ivanov VN. Radiation induced non-targeted response: mechanism and potential clinical implications. Curr Mol Pharmacol. 2011;4:96–105.

    PubMed  CAS  Google Scholar 

  12. Mothersill C, Seymour CB. Radiation-induced bystander effects—implications for cancer. Nat Rev Cancer. 2004;4:158–64.

    Article  PubMed  CAS  Google Scholar 

  13. Prise KM, O’Sullivan JM. Radiation-induced bystander signalling in cancer therapy. Nat Rev Cancer. 2009;9:351–60.

    Article  PubMed  CAS  Google Scholar 

  14. Buonanno M, de Toledo SM, Azzam EI. Increased frequency of spontaneous neoplastic transformation in progeny of bystander cells from cultures exposed to densely-ionizing radiation. PloS One. 2011;6:art. no. e21540.

    Google Scholar 

  15. Buonanno M, De Toledo SM, Pain D, Azzam EI. Long-term consequences of radiation-induced bystander effects depend on radiation quality and dose and correlate with oxidative stress. Radiat Res. 2011;175:405–15.

    Article  PubMed  CAS  Google Scholar 

  16. Ponnaiya B, Suzuki M, Tsuruoka C, Uchihori Y, Wei Y, Hei TK. Detection of chromosomal instability in bystander cells after Si490-ion irradiation. Radiat Res. 2011;176:280–90.

    Article  PubMed  CAS  Google Scholar 

  17. Cucinotta FA, Chappell LJ. Non-targeted effects and the dose response for heavy ion tumor induction. Mutat Res. 2010;687:49–53.

    Article  PubMed  CAS  Google Scholar 

  18. Hall EJ, Henry S. Kaplan Distinguished Scientist Award 2003. The crooked shall be made straight; dose-response relationships for carcinogenesis. Int J Radiat Biol. 2004;80:327–37.

    Article  PubMed  CAS  Google Scholar 

  19. Tubiana M. Can we reduce the incidence of second primary malignancies occurring after radiotherapy? A critical review. Radiother Oncol. 2009;91:4–15; discussion 1–3.

    Google Scholar 

  20. National Research Council. Health risks from exposure to low levels of ionizing radiation. Washington, DC: National Research Council of the National Academies; 2005.

    Google Scholar 

  21. Roth RA, Sharma SC, Katz R. Systematic evaluation of cellular radiosensitivity parameters. Phys Med Biol. 1976;21:491–503.

    Article  PubMed  CAS  Google Scholar 

  22. Goodhead DT. Spatial and temporal distribution of energy. Health Phys. 1988;55:231–40.

    Article  PubMed  CAS  Google Scholar 

  23. Ottolenghi A, Merzagora M, Paretzke HG. DNA complex lesions induced by protons and alpha-particles: track structure characteristics determining linear energy transfer and particle type dependence. Radiat Environ Biophys. 1997;36:97–103.

    Article  PubMed  CAS  Google Scholar 

  24. Goodhead DT. Energy deposition stochastics and track structure: what about the target? Radiat Prot Dosimetry. 2006;122:3–15.

    Article  PubMed  Google Scholar 

  25. Ward JF. Biochemistry of DNA lesions. Radiat Res Suppl. 1985;8:S103–11.

    Article  PubMed  CAS  Google Scholar 

  26. Georgakilas AG. From chemistry of DNA damage to repair and biological significance. Comprehending the future. Mutat Res. 2011;711:1–2.

    Article  PubMed  CAS  Google Scholar 

  27. Autsavapromporn N, de Toledo SM, Little JB, Jay-Gerin J-P, Harris AL, Azzam EI. The role of gap junction communication and oxidative stress in the propagation of toxic effects among high-dose α-particle-irradiated human cells. Radiat Res. 2011;175:347–57.

    Article  PubMed  CAS  Google Scholar 

  28. Sutherland BM, Bennett PV, Sidorkina O, Laval J. Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation. Proc Natl Acad Sci USA. 2000;97:103–8.

    Article  PubMed  CAS  Google Scholar 

  29. Nikjoo H, Goodhead DT, Charlton DE, Paretzke HG. Energy deposition in small cylindrical targets by monoenergetic electrons. Int J Radiat Biol. 1991;60:739–56.

    Article  PubMed  CAS  Google Scholar 

  30. de Toledo SM, Asaad N, Venkatachalam P, Li L, Howell RW, Spitz DR, et al. Adaptive responses to low-dose/low-dose-rate γ rays in normal human fibroblasts: the role of growth architecture and oxidative metabolism. Radiat Res. 2006;166:849–57.

    Article  PubMed  Google Scholar 

  31. Feinendegen LE, Pollycove M, Neumann RD. Whole-body responses to low-level radiation exposure: new concepts in mammalian radiobiology. Exp Hematol. 2007;35:37–46.

    Article  PubMed  CAS  Google Scholar 

  32. Wolff S. The adaptive response in radiobiology: evolving insights and implications. Environ Health Perspect. 1998;106 Suppl 1:277–83.

    Article  PubMed  Google Scholar 

  33. Nomura T, Li XH, Ogata H, Sakai K, Kondo T, Takano Y, et al. Suppressive effects of continuous low-dose-rate gamma irradiation on diabetic nephropathy in Type II diabetes mellitus model mice. Radiat Res. 2011;176:356–65.

    Article  PubMed  CAS  Google Scholar 

  34. Azzam EI. Exposure to low level environmental agents: the induction of hormesis. Mutat Res. 2011;726:89–90.

    Article  PubMed  CAS  Google Scholar 

  35. Kadhim MA, Macdonald DA, Goodhead DT, Lorimore SA, Marsden SJ, Wright EG. Transmission of chromosomal instability after plutonium α-particle irradiation [see comments]. Nature. 1992;355:738–40.

    Article  PubMed  CAS  Google Scholar 

  36. Kronenberg A, Gauny S, Criddle K, Vannais D, Ueno A, Kraemer S, et al. Heavy ion mutagenesis: linear energy transfer effects and genetic linkage. Radiat Environ Biophys. 1995;34:73–8.

    Article  PubMed  CAS  Google Scholar 

  37. Kronenberg A, Little JB. Molecular characterization of thymidine kinase mutants of human cells induced by densely ionizing radiation. Mutat Res. 1989;211:215–24.

    Article  PubMed  CAS  Google Scholar 

  38. Grosovsky AJ, Parks KK, Giver CR, Nelson SL. Clonal analysis of delayed karyotypic ­abnormalities and gene mutations in radiation-induced genetic instability. Mol Cell Biol. 1996;16:6252–62.

    PubMed  CAS  Google Scholar 

  39. Nagasawa H, Little JB. Induction of sister chromatid exchanges by extremely low doses of α-particles. Cancer Res. 1992;52:6394–6.

    PubMed  CAS  Google Scholar 

  40. Cucinotta FA, Katz R, Wilson JW. Radial distribution of electron spectra from high-energy ions. Radiat Environ Biophys. 1998;37:259–65.

    Article  PubMed  CAS  Google Scholar 

  41. Goodhead DT, Thacker J, Cox R. Effects of radiations of different qualities on cells: molecular mechanisms of damage and repair (Weiss Lecture). Int J Radiat Biol. 1993;63:543–56.

    Article  PubMed  CAS  Google Scholar 

  42. Muroya Y, Plante I, Azzam EI, Meesungnoen J, Katsumura Y, Jay-Gerin J-P. High-LET ion radiolysis of water: visualization of the formation and evolution of ion tracks and relevance to the radiation-induced bystander effect. Radiat Res. 2006;165:485–91.

    Article  PubMed  CAS  Google Scholar 

  43. Plante I, Ponomarev A, Cucinotta FA. 3D visualisation of the stochastic patterns of the radial dose in nano-volumes by a Monte Carlo simulation of HZE ion track structure. Radiat Prot Dosimetry. 2011;143:156–61.

    Article  PubMed  CAS  Google Scholar 

  44. Mikkelsen RB, Wardman P. Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms. Oncogene. 2003;22:5734–54.

    Article  PubMed  CAS  Google Scholar 

  45. Wu C, Parrott AM, Fu C, Liu T, Marino SM, Gladyshev VN, et al. Thioredoxin 1-mediated post-translational modifications: reduction, transnitrosylation, denitrosylation, and related proteomics methodologies. Antioxid Redox Signal. 2011;15:2565–604.

    Article  PubMed  CAS  Google Scholar 

  46. Formenti SC, Demaria S. Local control by radiotherapy: is that all there is? Breast Cancer Res. 2008;10:215.

    Article  PubMed  CAS  Google Scholar 

  47. Robbins ME, Zhao W. Chronic oxidative stress and radiation-induced late normal tissue injury: a review. Int J Radiat Biol. 2004;80:251–9.

    Article  PubMed  CAS  Google Scholar 

  48. Dedon PC, Tannenbaum SR. Reactive nitrogen species in the chemical biology of inflammation. Arch Biochem Biophys. 2004;423:12–22.

    Article  PubMed  CAS  Google Scholar 

  49. Cadet J, Douki T, Ravanat JL. Measurement of oxidatively generated base damage in cellular DNA. Mutat Res. 2011;711:3–12.

    Article  PubMed  CAS  Google Scholar 

  50. Deshpande A, Goodwin EH, Bailey SM, Marrone BL, Lehnert BE. Alpha-particle-induced sister chromatid exchange in normal human lung fibroblasts—evidence for an extranuclear target. Radiat Res. 1996;145:260–7.

    Article  PubMed  CAS  Google Scholar 

  51. Belyakov OV, Malcolmson AM, Folkard M, Prise KM, Michael BD. Direct evidence for a bystander effect of ionizing radiation in primary human fibroblasts. Br J Cancer. 2001;84:674–9.

    Article  PubMed  CAS  Google Scholar 

  52. Zhou H, Randers-Pehrson G, Waldren CA, Vannais D, Hall EJ, Hei TK. Induction of a bystander mutagenic effect of alpha particles in mammalian cells. Proc Natl Acad Sci USA. 2000;97:2099–104.

    Article  PubMed  CAS  Google Scholar 

  53. Azzam EI, de Toledo SM, Little JB. Direct evidence for the participation of gap-junction mediated intercellular communication in the transmission of damage signals from alpha-particle irradiated to non-irradiated cells. Proc Natl Acad Sci USA. 2001;98:473–8.

    PubMed  CAS  Google Scholar 

  54. Sawant SG, Randers-Pehrson G, Geard CR, Brenner DJ, Hall EJ. The bystander effect in radiation oncogenesis: I. Transformation in C3H 10T1/2 cells in vitro can be initiated in the unirradiated neighbors of irradiated cells. Radiat Res. 2001;155:397–401.

    Article  PubMed  CAS  Google Scholar 

  55. Ghandhi SA, Yaghoubian B, Amundson SA. Global gene expression analyses of bystander and alpha particle irradiated normal human lung fibroblasts: synchronous and differential responses. BMC Med Genomics. 2008;1:63.

    Article  PubMed  CAS  Google Scholar 

  56. Bishayee A, Rao DV, Howell RW. Evidence for pronounced bystander effects caused by nonuniform distributions of radioactivity using a novel three-dimensional tissue culture model. Radiat Res. 1999;152:88–97.

    Article  PubMed  CAS  Google Scholar 

  57. Gerashchenko BI, Howell RW. Cell proximity is a prerequisite for the proliferative response of bystander cells co-cultured with cells irradiated with gamma-rays. Cytometry. 2003;56A:71–80.

    Article  Google Scholar 

  58. Mothersill C, Seymour C. Survival of human epithelial cells irradiated with cobalt 60 as microcolonies or single cells. Int J Radiat Biol. 1997;72:597–606.

    Article  PubMed  CAS  Google Scholar 

  59. Xue LY, Butler NJ, Makrigiorgos GM, Adelstein SJ, Kassis AI. Bystander effect produced by radiolabeled tumor cells in vivo. Proc Natl Acad Sci USA. 2002;99:13765–70.

    Article  PubMed  CAS  Google Scholar 

  60. Persaud R, Zhou H, Baker SE, Hei TK, Hall EJ. Assessment of low linear energy transfer radiation-induced bystander mutagenesis in a three-dimensional culture model. Cancer Res. 2005;65:9876–82.

    Article  PubMed  CAS  Google Scholar 

  61. Held KD. Effects of low fluences of radiations found in space on cellular systems. Int J Radiat Biol. 2009;85:379–90.

    Article  PubMed  CAS  Google Scholar 

  62. Matsumoto H, Hayashi S, Hatashita M, Shioura H, Ohtsubo T, Kitai R, et al. Induction of radioresistance to accelerated carbon-ion beams in recipient cells by nitric oxide excreted from irradiated donor cells of human glioblastoma. Int J Radiat Biol. 2000;76:1649–57.

    Article  PubMed  CAS  Google Scholar 

  63. Azzam EI, Little JB. The radiation-induced bystander effect: evidence and significance. Hum Exp Toxicol. 2004;23:61–5.

    Article  PubMed  Google Scholar 

  64. Akudugu JM, Azzam EI, Howell RW. Induction of lethal bystander effects in human breast cancer cell cultures by DNA-incorporated iodine-125 depends on phenotype. Int J Radiat Biol. 2012 April 10; Epub ahead of print.

    Google Scholar 

  65. Mothersill C, Seymour C. Medium from irradiated human epithelial cells but not human fibroblasts reduces the clonogenic survival of unirradiated cells. Int J Radiat Biol. 1997;71:421–7.

    Article  PubMed  CAS  Google Scholar 

  66. Mothersill C, Seymour C. Radiation-induced bystander effects, carcinogenesis and models. Oncogene. 2003;22:7028–33.

    Article  PubMed  CAS  Google Scholar 

  67. Mothersill C, Seymour CB. Cell-cell contact during gamma irradiation is not required to induce a bystander effect in normal human keratinocytes: evidence for release during irradiation of a signal controlling survival into the medium. Radiat Res. 1998;149:252–62.

    Article  Google Scholar 

  68. Morgan WF. Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects. Radiat Res. 2003;159:581–96.

    Article  PubMed  CAS  Google Scholar 

  69. Mothersill C, Seymour C. Radiation-induced bystander effects: past history and future directions. Radiat Res. 2001;155:759–67.

    Article  PubMed  CAS  Google Scholar 

  70. Hamada N, Maeda M, Otsuka K, Tomita M. Signaling pathways underpinning the manifestations of ionizing radiation-induced bystander effects. Curr Mol Pharmacol. 2011;4:79–95.

    PubMed  CAS  Google Scholar 

  71. Blyth BJ, Sykes PJ. Radiation-induced bystander effects: what are they, and how relevant are they to human radiation exposures? Radiat Res. 2011;176:139–57.

    Article  PubMed  CAS  Google Scholar 

  72. Hei TK, Zhou H, Ivanov VN, Hong M, Lieberman HB, Brenner DJ, et al. Mechanism of radiation-induced bystander effects: a unifying model. J Pharm Pharmacol. 2008;60:943–50.

    Article  PubMed  CAS  Google Scholar 

  73. Little JB. Genomic instability and bystander effects: a historical perspective. Oncogene. 2003;22:6978–87.

    Article  PubMed  CAS  Google Scholar 

  74. Azzam EI, de Toledo SM, Spitz DR, Little JB. Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from alpha-particle-irradiated normal human fibroblast cultures. Cancer Res. 2002;62:5436–42.

    PubMed  CAS  Google Scholar 

  75. Zhou HN, Suzuki M, Randers-Pehrson R, Chen G, Trosko J, Vannais D, et al. Radiation risk at low doses may be greater than we thought. Proc Natl Acad Sci USA. 2001;98:14410–5.

    Article  PubMed  CAS  Google Scholar 

  76. Ghandhi SA, Sinha A, Markatou M, Amundson SA. Time-series clustering of gene expression in irradiated and bystander fibroblasts: an application of FBPA clustering. BMC Genomics. 2011;12:2.

    Article  PubMed  CAS  Google Scholar 

  77. Belyakov OV, Mitchell SA, Parikh D, Randers-Pehrson G, Marino SA, Amundson SA, et al. Biological effects in unirradiated human tissue induced by radiation damage up to 1 mm away. Proc Natl Acad Sci USA. 2005;102:14203–8.

    Article  PubMed  CAS  Google Scholar 

  78. Sedelnikova OA, Nakamura A, Kovalchuk O, Koturbash I, Mitchell SA, Marino SA, et al. DNA double-strand breaks form in bystander cells after microbeam irradiation of three-dimensional human tissue models. Cancer Res. 2007;67:4295–302.

    Article  PubMed  CAS  Google Scholar 

  79. Kovalchuk O, Zemp FJ, Filkowski J, Altamirano A, Dickey JS, Jenkins-Baker G, et al. MicroRNAome changes in bystander three-dimensional human tissue models suggest priming of apoptotic pathways. Carcinogenesis. 2010;31:1882–8.

    Article  PubMed  CAS  Google Scholar 

  80. Lorimore SA, Coates PJ, Scobie GE, Milne G, Wright EG. Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects? Oncogene. 2001;20:7085–95.

    Article  PubMed  CAS  Google Scholar 

  81. Koturbash I, Kutanzi K, Hendrickson K, Rodriguez-Juarez R, Kogosov D, Kovalchuk O. Radiation-induced bystander effects in vivo are sex specific. Mutat Res. 2008;642:28–36.

    Article  PubMed  CAS  Google Scholar 

  82. Jain MR, Li M, Chen W, Liu T, De Toledo SM, Pandey BN, et al. In vivo space radiation-induced non-targeted responses: late effects on molecular signaling in mitochondria. Curr Mol Pharmacol. 2011;4:106–14.

    PubMed  CAS  Google Scholar 

  83. Brooks AL, Retherford JC, McClellan RO. Effect of 239PuO2 particle number and size on the frequency and distribution of chromosome aberrations in the liver of the Chinese hamster. Radiat Res. 1974;59:693–709.

    Article  PubMed  CAS  Google Scholar 

  84. Brooks AL, Benjamin SA, Hahn FF, Brownstein DG, Griffith WC, McClellan RO. The induction of liver tumors by 239Pu citrate or 239PuO2 particles in the Chinese hamster. Radiat Res. 1983;96:135–51.

    Article  PubMed  CAS  Google Scholar 

  85. Mancuso M, Pasquali E, Leonardi S, Tanori M, Rebessi S, Di Majo V, et al. Oncogenic bystander radiation effects in patched heterozygous mouse cerebellum. Proc Natl Acad Sci USA. 2008;105:12445–50.

    Article  PubMed  CAS  Google Scholar 

  86. Blakely EA. Biological effects of cosmic radiation: deterministic and stochastic. Health Phys. 2000;79:495–506.

    Article  PubMed  CAS  Google Scholar 

  87. Charlton DE, Sephton R. A relationship between microdosimetric spectra and cell survival for high-LET irradiation. Int J Radiat Biol. 1991;59:447–57.

    Article  PubMed  CAS  Google Scholar 

  88. Cucinotta F, Nikjoo H, Goodhead DT. The effect of delta rays on the number of particle traversals per cell in laboratory and space exposures. Radiat Res. 1998;150:115–9.

    Article  PubMed  CAS  Google Scholar 

  89. National Research Council. Managing space radiation risk in the new era of space exploration. Washington, DC: The National Academies Press; 2008.

    Google Scholar 

  90. Hollowell Jr JG, Littlefield LG. Chromosome damage induced by plasma of x-rayed patients: an indirect effect of x-ray. Proc Soc Exp Biol Med. 1968;129:240–4.

    PubMed  Google Scholar 

  91. Goh K, Sumner H. Breaks in normal human chromosomes: are they induced by a transferable substance in the plasma of persons exposed to total-body irradiation? Radiat Res. 1968;35:171–81.

    Article  PubMed  CAS  Google Scholar 

  92. Morgan WF, Day JP, Kaplan MI, McGhee EM, Limoli CL. Genomic instability induced by ionizing radiation. Radiat Res. 1996;146:247–58.

    Article  PubMed  CAS  Google Scholar 

  93. Kadhim MA, Lorimore SA, Hepburn MD, Goodhead DT, Buckle VJ, Wright EG. Alpha-particle-induced chromosomal instability in human bone marrow cells. Lancet. 1994;344:987–8.

    Article  PubMed  CAS  Google Scholar 

  94. Kennedy AR, Fox M, Murphy G, Little JB. Relationship between X-ray exposure and malignant transformation in C3H 10T1/2 cells. Proc Natl Acad Sci. 1980;77:7262–6.

    Article  PubMed  CAS  Google Scholar 

  95. Kennedy AR, Little JB. Evidence that a second event in X-ray induced oncogenic transformation in vitro occurs during cellular proliferation. Radiat Res. 1984;99:228–48.

    Article  PubMed  CAS  Google Scholar 

  96. Sabatier L, Dutrillaux B, Martin MB. Chromosomal instability. Nature. 1992;357:548.

    Article  PubMed  CAS  Google Scholar 

  97. Chang WP, Little JB. Persistently elevated frequency of spontaneous mutations in progeny of CHO clones surviving X-irradiation: association with delayed reproductive death phenotype. Mutat Res. 1992;270:191–9.

    Article  PubMed  CAS  Google Scholar 

  98. Seymour CB, Mothersill C, Alper T. High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol Relat Stud Phys Chem Med. 1986;50:167–79.

    Article  PubMed  CAS  Google Scholar 

  99. Chang WP, Little JB. Delayed reproductive death as a dominant phenotype in cell clones surviving X-irradiation. Carcinogenesis. 1992;13:923–8.

    Article  PubMed  CAS  Google Scholar 

  100. Belyakov OV, Prise KM, Trott KR, Michael BD. Delayed lethality, apoptosis and micronucleus formation in human fibroblasts irradiated with X-rays or alpha-particles. Int J Radiat Biol. 1999;75:985–93.

    Article  PubMed  CAS  Google Scholar 

  101. Lorimore SA, Kadhim MA, Pocock DA, Papworth D, Stevens DL, Goodhead DT, et al. Chromosomal instability in the descendants of unirradiated surviving cells after alpha-particle irradiation. Proc Natl Acad Sci USA. 1998;95:5730–3.

    Article  PubMed  CAS  Google Scholar 

  102. Wu LJ, Randers-Pehrson GR, Xu A, Waldren CA, Geard CR, Yu ZL, et al. Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells. Proc Natl Acad Sci USA. 1999;96:4959–64.

    Article  PubMed  CAS  Google Scholar 

  103. Prise KM, Belyakov OV, Folkard M, Micheal BD. Studies on bystander effects in human fibroblasts using a charged particle microbeam. Int J Radiat Biol. 1998;74:793–8.

    Article  PubMed  CAS  Google Scholar 

  104. Lehnert BE, Goodwin EH. Extracellular factor(s) following exposure to alpha particles can cause sister chromatid exchanges in normal human cells. Cancer Res. 1997;57:2164–71.

    PubMed  CAS  Google Scholar 

  105. Zhou H, Suzuki M, Geard CR, Hei TK. Effects of irradiated medium with or without cells on bystander cell responses. Mutat Res. 2002;499:135–41.

    Article  PubMed  CAS  Google Scholar 

  106. Hu B, Shen B, Su Y, Geard CR, Balajee AS. Protein kinase C epsilon is involved in ionizing radiation induced bystander response in human cells. Int J Biochem Cell Biol. 2009;41:2413–21.

    Article  PubMed  CAS  Google Scholar 

  107. Narayanan PK, Goodwin EH, Lehnert BE. Alpha particles initiate biological production of superoxide anions and hydrogen peroxide in human cells. Cancer Res. 1997;57:3963–71.

    PubMed  CAS  Google Scholar 

  108. Abdelrazzak AB, Stevens DL, Bauer G, O’Neill P, Hill MA. The role of radiation quality in the stimulation of intercellular induction of apoptosis in transformed cells at very low doses. Radiat Res. 2011;176:346–55.

    Article  PubMed  CAS  Google Scholar 

  109. Dickey JS, Baird BJ, Redon CE, Sokolov MV, Sedelnikova OA, Bonner WM. Intercellular communication of cellular stress monitored by gamma-H2AX induction. Carcinogenesis. 2009;30:1686–95.

    Article  PubMed  CAS  Google Scholar 

  110. Shao C, Folkard M, Prise KM. Role of TGF-beta1 and nitric oxide in the bystander response of irradiated glioma cells. Oncogene. 2008;27:434–40.

    Article  PubMed  CAS  Google Scholar 

  111. Narayanan PK, LaRue KEA, Goodwin EH, Lehnert BE. Alpha particles induce the production of interleukin-8 by human cells. Radiat Res. 1999;152:57–63.

    Article  PubMed  CAS  Google Scholar 

  112. Zhou H, Ivanov VN, Gillespie J, Geard CR, Amundson SA, Brenner DJ, et al. Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway. Proc Natl Acad Sci USA. 2005;102:14641–6.

    Article  PubMed  CAS  Google Scholar 

  113. Ivanov VN, Zhou H, Ghandhi SA, Karasic TB, Yaghoubian B, Amundson SA, et al. Radiation-induced bystander signaling pathways in human fibroblasts: a role for interleukin-33 in the signal transmission. Cell Signal. 2010;22:1076–87.

    Article  PubMed  CAS  Google Scholar 

  114. Kalanxhi E, Dahle J. Genome-wide microarray analysis of human fibroblasts in response to gamma radiation and the radiation-induced bystander effect. Radiat Res. 2012;177:35–43.

    Article  PubMed  CAS  Google Scholar 

  115. Asur R, Balasubramaniam M, Marples B, Thomas RA, Tucker JD. Bystander effects induced by chemicals and ionizing radiation: evaluation of changes in gene expression of downstream MAPK targets. Mutagenesis. 2010;25:271–9.

    Article  PubMed  CAS  Google Scholar 

  116. Chaudhry MA, Omaruddin RA. Mitochondrial gene expression in directly irradiated and nonirradiated bystander cells. Cancer Biother Radiopharm. 2011;26(5):657–63.

    Article  PubMed  CAS  Google Scholar 

  117. Herok R, Konopacka M, Polanska J, Swierniak A, Rogolinski J, Jaksik R, et al. Bystander effects induced by medium from irradiated cells: similar transcriptome responses in irradiated and bystander K562 cells. Int J Radiat Oncol Biol Phys. 2010;77:244–52.

    Article  PubMed  CAS  Google Scholar 

  118. Chaudhry MA. Bystander effect: biological endpoints and microarray analysis. Mutat Res. 2006;597:98–112.

    Article  PubMed  CAS  Google Scholar 

  119. Iwakawa M, Hamada N, Imadome K, Funayama T, Sakashita T, Kobayashi Y, et al. Expression profiles are different in carbon ion-irradiated normal human fibroblasts and their bystander cells. Mutat Res. 2008;642:57–67.

    Article  PubMed  CAS  Google Scholar 

  120. Ghandhi SA, Ming L, Ivanov VN, Hei TK, Amundson SA. Regulation of early signaling and gene expression in the alpha-particle and bystander response of IMR-90 human fibroblasts. BMC Med Genomics. 2010;3:31.

    Article  PubMed  CAS  Google Scholar 

  121. Iyer R, Lehnert BE. Factors underlying the cell growth-related bystander responses to alpha particles. Cancer Res. 2000;60:1290–8.

    PubMed  CAS  Google Scholar 

  122. Shao C, Furusawa Y, Aoki M, Matsumoto H, Ando K. Nitric oxide-mediated bystander effect induced by heavy-ions in human salivary gland tumour cells. Int J Radiat Biol. 2002;78:837–44.

    Article  PubMed  CAS  Google Scholar 

  123. Azzam EI, de Toledo SM, Waker AJ, Little JB. High and low fluences of alpha-particles induce a G1 checkpoint in human diploid fibroblasts. Cancer Res. 2000;60:2623–31.

    PubMed  CAS  Google Scholar 

  124. Lyng FM, Seymour CB, Mothersill C. Initiation of apoptosis in cells exposed to medium from the progeny of irradiated cells: a possible mechanism for bystander-induced genomic instability? Radiat Res. 2002;157:365–70.

    Article  PubMed  CAS  Google Scholar 

  125. Nagar S, Smith LE, Morgan WF. Characterization of a novel epigenetic effect of ionizing radiation: the death-inducing effect. Cancer Res. 2003;63:324–8.

    PubMed  CAS  Google Scholar 

  126. Azzam EI, de Toledo SM, Gooding T, Little JB. Intercellular communication is involved in the bystander regulation of gene expression in human cells exposed to very low fluences of alpha particles. Radiat Res. 1998;150:497–504.

    Article  PubMed  CAS  Google Scholar 

  127. Shao C, Furusawa Y, Kobayashi Y, Funayama T, Wada S. Bystander effect induced by counted high-LET particles in confluent human fibroblasts: a mechanistic study. FASEB J. 2003;17:1422–7.

    Article  PubMed  CAS  Google Scholar 

  128. Harada K, Nonaka T, Hamada N, Sakurai H, Hasegawa M, Funayama T, et al. ­Heavy-ion-induced bystander killing of human lung cancer cells: role of gap junctional intercellular communication. Cancer Sci. 2009;100:684–8.

    Article  PubMed  CAS  Google Scholar 

  129. Suzuki M, Tsuruoka C. Heavy charged particles produce a bystander effect via cell-cell junctions. Biol Sci Space. 2004;18:241–6.

    Article  PubMed  Google Scholar 

  130. Vance MM, Wiley LM. Gap junction intercellular communication mediates the competitive cell proliferation disadvantage of irradiated mouse preimplantation embryos in aggregation chimeras. Radiat Res. 1999;152:544–51.

    Article  PubMed  CAS  Google Scholar 

  131. Mitchell SA, Randers-Pehrson G, Brenner DJ, Hall EJ. The bystander response in C3H 10T1/2 cells: the influence of cell-to-cell contact. Radiat Res. 2004;161:397–401.

    Article  PubMed  CAS  Google Scholar 

  132. Autsavapromporn N, de Toledo SM, Buonanno M, Jay-Gerin JP, Harris AL, Azzam EI. Intercellular communication amplifies stressful effects in high-charge, high-energy (HZE) particle-irradiated human cells. J Radiat Res (Tokyo). 2011;52:408–14.

    Article  CAS  Google Scholar 

  133. Harris AL. Emerging issues of connexin channels: biophysics fills the gap. Q Rev Biophys. 2001;34:325–472.

    PubMed  CAS  Google Scholar 

  134. Hall EJ, Hei TK. Genomic instability and bystander effects induced by high-LET radiation. Oncogene. 2003;22:7034–42.

    Article  PubMed  CAS  Google Scholar 

  135. Azzam EI, de Toledo SM, Little JB. Expression of CONNEXIN43 is highly sensitive to ionizing radiation and environmental stresses. Cancer Res. 2003;63:7128–35.

    PubMed  CAS  Google Scholar 

  136. Schubert AL, Schubert W, Spray DC, Lisanti MP. Connexin family members target to lipid raft domains and interact with caveolin-1. Biochemistry. 2002;41:5754–64.

    Article  PubMed  CAS  Google Scholar 

  137. Nagasawa H, Cremesti A, Kolesnick R, Fuks Z, Little JB. Involvement of membrane signaling in the bystander effect in irradiated cells. Cancer Res. 2002;62:2531–4.

    PubMed  CAS  Google Scholar 

  138. Jensen R, Glazer PM. Cell-interdependent cisplatin killing by Ku/DNA-dependent protein kinase signaling transduced through gap junctions. Proc Natl Acad Sci USA. 2004;101:6134–9.

    Article  PubMed  CAS  Google Scholar 

  139. Kalvelyte A, Imbrasaite A, Bukauskiene A, Verselis VK, Bukauskas FF. Connexins and apoptotic transformation. Biochem Pharmacol. 2003;66:1661–72.

    Article  PubMed  CAS  Google Scholar 

  140. Tanaka M, Grossman HB. Connexin 26 gene therapy of human bladder cancer: induction of growth suppression, apoptosis, and synergy with Cisplatin. Hum Gene Ther. 2001;12:2225–36.

    Article  PubMed  CAS  Google Scholar 

  141. Hong X, Wang Q, Yang Y, Zheng S, Tong X, Zhang S, et al. Gap junctions propagate opposite effects in normal and tumor testicular cells in response to cisplatin. Cancer Lett. 2012;317(2):165–71.

    Article  PubMed  CAS  Google Scholar 

  142. Fick J, Barker II FD, Dazin P, Westphale EM, Beyer E, Israel MA. The extent of hepatocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro. Proc Natl Acad Sci USA. 1995;92:11071–5.

    Article  PubMed  CAS  Google Scholar 

  143. Freeman SM, Abboud CN, Whartenby KA, Packman CH, Koeplin DS, Moolten FL, et al. The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res. 1993;53:5274–83.

    PubMed  CAS  Google Scholar 

  144. Kuriyama S, Nakatani T, Masui K, Sakamoto T, Tominaga K, Yoshikawa M, et al. Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma. Hepatology. 1995;22:1838–46.

    PubMed  CAS  Google Scholar 

  145. Mesnil M, Piccoli C, Tiraby G, Willecke K, Yamasaki H. Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Proc Natl Acad Sci USA. 1996;93:1831–5.

    Article  PubMed  CAS  Google Scholar 

  146. van Dillen IJ, Mulder NH, Vaalburg W, de Vries EF, Hospers GA. Influence of the bystander effect on HSV-tk/GCV gene therapy. A review. Curr Gene Ther. 2002;2:307–22.

    Article  PubMed  Google Scholar 

  147. Hamada N, Kodama S, Suzuki K, Watanabe M. Gap junctional intercellular communication and cellular response to heat stress. Carcinogenesis. 2003;24:1723–8.

    Article  PubMed  CAS  Google Scholar 

  148. Loewenstein WR, Rose B. The cell-cell channel in the control of growth. Semin Cell Biol. 1992;3:59–79.

    Article  PubMed  CAS  Google Scholar 

  149. Trosko JE, Chang CC, Madhukar BV, Klaunig JE. Chemical, oncogene and growth factor inhibition gap junctional intercellular communication: an integrative hypothesis of carcinogenesis. Pathobiology. 1990;58:265–78.

    Article  PubMed  CAS  Google Scholar 

  150. Yamasaki H, Mesnil M, Omori Y, Mironov N, Krutovskikh V. Intercellular communication and carcinogenesis. Mutat Res. 1995;333:181–8.

    Article  PubMed  CAS  Google Scholar 

  151. Mehta PP, Bertram JS, Loewenstein WR. Growth inhibition of transformed cells correlates with their junctional communication with normal cells. Cell. 1986;44:187–96.

    Article  PubMed  CAS  Google Scholar 

  152. Yamasaki H, Naus CC. Role of connexin genes in growth control. Carcinogenesis. 1996;17:1199–213.

    Article  PubMed  CAS  Google Scholar 

  153. Willecke K, Eiberger J, Degen J, Eckardt D, Romualdi A, Guldenagel M, et al. Structural and functional diversity of connexin genes in the mouse and human genome. Biol Chem. 2002;383:725–37.

    Article  PubMed  CAS  Google Scholar 

  154. Bedner P, Niessen H, Odermatt B, Kretz M, Willecke K, Harz H. Selective permeability of different connexin channels to the second messenger cyclic AMP. J Biol Chem. 2005;281:6673–81.

    Article  PubMed  CAS  Google Scholar 

  155. Goldberg GS, Moreno AP, Lampe PD. Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP. J Biol Chem. 2002;277:36725–30.

    Article  PubMed  CAS  Google Scholar 

  156. Niessen H, Harz H, Bedner P, Kramer K, Willecke K. Selective permeability of different connexin channels to the second messenger inositol 1,4,5-trisphosphate. J Cell Sci. 2000;113(Pt 8):1365–72.

    PubMed  CAS  Google Scholar 

  157. Bevans CG, Kordel M, Rhee SK, Harris AL. Isoform composition of connexin channels determines selectivity among second messengers and uncharged molecules. J Biol Chem. 1998;273:2808–16.

    Article  PubMed  CAS  Google Scholar 

  158. Elsayed W, Harris AL. Selective permeability of connexin channels among inositol phosphates. Biophys J. 2004;86:583a.

    Google Scholar 

  159. Elsayed WA, Koreen IV, Liu YL, Harris AL. Inositol phosphates are selectively permeable through heteromeric connexin channels. Mol Biol Cell. 2004;15:183a.

    Google Scholar 

  160. Locke D, Stein T, Davies C, Morris J, Harris AL, Evans WH, et al. Altered permeability and modulatory character of connexin channels during mammary gland development. Exp Cell Res. 2004;298:643–60.

    Article  PubMed  CAS  Google Scholar 

  161. Ayad WA, Locke D, Koreen IV, Harris AL. Heteromeric, but not homomeric, connexin channels are selectively permeable to inositol phosphates. J Biol Chem. 2006;281:16727–39.

    Article  PubMed  CAS  Google Scholar 

  162. Cronier L, Crespin S, Strale PO, Defamie N, Mesnil M. Gap junctions and cancer: new functions for an old story. Antioxid Redox Signal. 2009;11:323–38.

    Article  PubMed  CAS  Google Scholar 

  163. Mesnil M, Crespin S, Avanzo JL, Zaidan-Dagli ML. Defective gap junctional intercellular communication in the carcinogenic process. Biochim Biophys Acta. 2005;1719:125–45.

    Article  PubMed  CAS  Google Scholar 

  164. Ammerpohl O, Trauzold A, Schniewind B, Griep U, Pilarsky C, Grutzmann R, et al. Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells. Br J Cancer. 2007;96:73–81.

    Article  PubMed  CAS  Google Scholar 

  165. Chen W, Yan C, Hou J, Pu J, Ouyang J, Wen D. ATRA enhances bystander effect of suicide gene therapy in the treatment of prostate cancer. Urol Oncol. 2008;26:397–405.

    Article  PubMed  CAS  Google Scholar 

  166. Xing Y, Lu G, Xiao Y, Zeng F, Zhang Q, Xiong P, et al. [Bystander effect mediated by herpes simplex virus-thymidine kinase/ganciclovir approach on prostatic cancer cells and its regulation]. Zhonghua Yi Xue Za Zhi. 2002;82:1484–7.

    PubMed  CAS  Google Scholar 

  167. Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82:47–95.

    PubMed  CAS  Google Scholar 

  168. Burdon RH. Control of cell proliferation by reactive oxygen species. Biochem Soc Trans. 1996;24:1028–32.

    PubMed  CAS  Google Scholar 

  169. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408:239–47.

    Article  PubMed  CAS  Google Scholar 

  170. Bishayee A, Hill HZ, Stein D, Rao DV, Howell RW. Free-radical initiated and gap junction-mediated bystander effect due to nonuniform distribution of incorporated radioactivity in a three-dimensional tissue culture model. Radiat Res. 2001;155:335–44.

    Article  PubMed  CAS  Google Scholar 

  171. Lyng FM, Seymour CB, Mothersill C. Production of a signal by irradiated cells which leads to a response in unirradiated cells characteristic of initiation of apoptosis. Br J Cancer. 2000;83:1223–30.

    Article  PubMed  CAS  Google Scholar 

  172. Lyng FM, Seymour CB, Mothersill C. Oxidative stress in cells exposed to low levels of ionizing radiation. Biochem Soc Trans. 2001;29:350–3.

    Article  PubMed  CAS  Google Scholar 

  173. Mothersill C, Stamato TD, Perez ML, Cummins R, Mooney R, Seymour C. Involvement of energy metabolism in the production of ‘bystander effects’ by radiation. Br J Cancer. 2000;82:1740–6.

    Article  PubMed  CAS  Google Scholar 

  174. Khan MA, Hill RP, Van Dyk J. Partial volume rat lung irradiation: an evaluation of early DNA damage. Int J Radiat Oncol Biol Phys. 1998;40:467–76.

    Article  PubMed  CAS  Google Scholar 

  175. Matsumoto H, Hayashi S, Hatashita M, Ohnishi K, Shioura H, Ohtsubo T, et al. Induction of radioresistance by a nitric oxide-mediated bystander effect. Radiat Res. 2001;155:387–96.

    Article  PubMed  CAS  Google Scholar 

  176. Shao C, Stewart V, Folkard M, Michael BD, Prise KM. Nitric oxide-mediated signaling in the bystander response of individually targeted glioma cells. Cancer Res. 2003;63:8437–42.

    PubMed  CAS  Google Scholar 

  177. Huo L, Nagasawa H, Little JB. HPRT mutants induced in bystander cells by very low fluences of alpha particles result primarily from point mutations. Radiat Res. 2001;156:521–5.

    Article  PubMed  CAS  Google Scholar 

  178. Halliwell B. Free radicals, proteins and DNA: oxidative damage versus redox regulation. Biochem Soc Trans. 1996;24:1023–7.

    PubMed  CAS  Google Scholar 

  179. Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA. 1993;90:7915–22.

    Article  PubMed  CAS  Google Scholar 

  180. Emerit I. Reactive oxygen species, chromosome mutation, and cancer: possible role of clastogenic factors in carcinogenesis. Free Radic Biol Med. 1994;16:99–109.

    Article  PubMed  CAS  Google Scholar 

  181. Cerutti P, Ghosh R, Oya Y, Amstad P. The role of the cellular antioxidant defense in oxidant carcinogenesis. Environ Health Perspect. 1994;102 Suppl 10:123–9.

    Article  PubMed  CAS  Google Scholar 

  182. Lampe PD, Lau AF. Regulation of gap junctions by phosphorylation of connexins. Arch Biochem Biophys. 2000;384:205–15.

    Article  PubMed  CAS  Google Scholar 

  183. Echetebu CO, Ali M, Izban MG, MacKay L, Garfield RE. Localization of regulatory protein binding sites in the proximal region of human myometrial connexin 43 gene. Mol Hum Reprod. 1999;5:757–66.

    Article  PubMed  CAS  Google Scholar 

  184. Ackerman WE, Robinson JM, Kniss DA. Despite transcriptional and functional coordination, cyclooxygenase-2 and microsomal prostaglandin E synthase-1 largely reside in distinct lipid microdomains in WISH epithelial cells. J Histochem Cytochem. 2005;53:1391–401.

    Article  PubMed  CAS  Google Scholar 

  185. Zhu A, Zhou H, Leloup C, Marino SA, Geard CR, Hei TK, et al. Differential impact of mouse Rad9 deletion on ionizing radiation-induced bystander effects. Radiat Res. 2005;164:655–61.

    Article  PubMed  CAS  Google Scholar 

  186. Lieberman HB. Rad9, an evolutionarily conserved gene with multiple functions for preserving genomic integrity. J Cell Biochem. 2006;97:690–7.

    Article  PubMed  CAS  Google Scholar 

  187. Nagasawa H, Little JB. Bystander effect for chromosomal aberrations induced in wild-type and repair deficient CHO cells by low fluences of alpha particles. Mutat Res. 2002;508:121–9.

    Article  PubMed  CAS  Google Scholar 

  188. Weill D, Gay F, Tovey MG, Chouaib S. Induction of tumor necrosis factor alpha expression in human T lymphocytes following ionizing gamma irradiation. J Interferon Cytokine Res. 1996;16:395–402.

    Article  PubMed  CAS  Google Scholar 

  189. Hosoi Y, Miyachi H, Matsumoto Y, Enomoto A, Nakagawa K, Suzuki N, et al. Induction of interleukin-1beta and interleukin-6 mRNA by low doses of ionizing radiation in macrophages. Int J Cancer. 2001;96:270–6.

    Article  PubMed  CAS  Google Scholar 

  190. Sawant SG, Randers-Pehrson G, Metting NF, Hall EJ. Adaptive response and the bystander effect induced by radiation in C3H 10T(1/2) cells in culture. Radiat Res. 2001;156:177–80.

    Article  PubMed  CAS  Google Scholar 

  191. Little JB, Nagasawa H, Li GC, Chen DJ. Involvement of the nonhomologous end joining DNA repair pathway in the bystander effect for chromosomal aberrations. Radiat Res. 2003;159:262–7.

    Article  PubMed  CAS  Google Scholar 

  192. Ward JF. The radiation-induced lesions which trigger the bystander effect. Mutat Res. 2002;499:151–4.

    Article  PubMed  CAS  Google Scholar 

  193. Jay-Gerin JP, Meesungnoen J, Banville P, Mankhetkorn S. Comment on “The radiation-induced lesions which trigger the bystander effect” by J.F. Ward [Mutat. Res. 499 (2002) 151–154]. Mutat Res. 2003;525:125–7.

    Article  PubMed  CAS  Google Scholar 

  194. Brenner DJ, Little JB, Sachs RK. The bystander effect in radiation oncogenesis: II. A quantitative model. Radiat Res. 2001;155:402–8.

    Article  PubMed  CAS  Google Scholar 

  195. Little MP, Wakeford R. The bystander effect in C3H 10T cells and radon-induced lung ­cancer. Radiat Res. 2001;156:695–9.

    Article  PubMed  CAS  Google Scholar 

  196. NAS. Health effects of exposure to radon (BEIR VI). Washington, DC: National Academy Press; 1998.

    Google Scholar 

  197. Little JB. What are the risks of low-level exposure to alpha radiation from radon? Proc Natl Acad Sci USA. 1997;94:5996–7.

    Article  PubMed  CAS  Google Scholar 

  198. Rees GJ, Ross CM. Abscopal regression following radiotherapy for adenocarcinoma. Br J Radiol. 1983;56:63–6.

    Article  PubMed  CAS  Google Scholar 

  199. Ohba K, Omagari K, Nakamura T, Ikuno N, Saeki S, Matsuo I, et al. Abscopal regression of hepatocellular carcinoma after radiotherapy for bone metastasis. Gut. 1998;43:575–7.

    Article  PubMed  CAS  Google Scholar 

  200. Uchida A, Mizutani Y, Nagamuta M, Ikenaga M. Effects of X-ray irradiation on natural killer (NK) cell system. I. Elevation of sensitivity of tumor cells and lytic function of NK cells. Immunopharmacol Immunotoxicol. 1989;11:507–19.

    Article  PubMed  CAS  Google Scholar 

  201. Camphausen K, Moses MA, Menard C, Sproull M, Beecken WD, Folkman J, et al. Radiation abscopal antitumor effect is mediated through p53. Cancer Res. 2003;63:1990–3.

    PubMed  CAS  Google Scholar 

  202. Komarova EA, Diatchenko L, Rokhlin OW, Hill JE, Wang ZJ, Krivokrysenko VI, et al. Stress-induced secretion of growth inhibitors: a novel tumor suppressor function of p53. Oncogene. 1998;17:1089–96.

    Article  PubMed  CAS  Google Scholar 

  203. Mothersill C, Seymour CB. Bystander and delayed effects after fractionated radiation exposure. Radiat Res. 2002;158:626–33.

    Article  PubMed  CAS  Google Scholar 

  204. Mothersill C, O’Malley K, Seymour CB. Characterisation of a bystander effect induced in human tissue explant cultures by low let radiation. Radiat Prot Dosimetry. 2002;99:163–7.

    Article  PubMed  CAS  Google Scholar 

  205. Mesnil M, Yamasaki H. Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication. Cancer Res. 2000;60:3989–99.

    PubMed  CAS  Google Scholar 

  206. Krutovskikh VA, Piccoli C, Yamasaki H. Gap junction intercellular communication propagates cell death in cancerous cells. Oncogene. 2002;21:1989–99.

    Article  PubMed  CAS  Google Scholar 

  207. Kennel SJ, Mirzadeh S. Vascular targeted radioimmunotherapy with 213Bi—an alpha-particle emitter. Nucl Med Biol. 1998;25:241–6.

    Article  PubMed  CAS  Google Scholar 

  208. Huneke RB, Pippin CG, Squire RA, Brechbiel MW, Gansow OA, Strand M. Effective α-particle-mediated radioimmunotherapy of murine leukemia. Cancer Res. 1992;52:5818–20.

    PubMed  CAS  Google Scholar 

  209. Fisher DR. Alpha-particle emitters in medicine. In: Adelstein SJ, Kassis AI, Burt RW, editors. Dosimetry of administered radionuclides. Washington, DC: American College of Nuclear Physicians; 1990. p. 194–214.

    Google Scholar 

  210. Sigurdson AJ, Jones IM. Second cancers after radiotherapy: any evidence for radiation-induced genomic instability? Oncogene. 2003;22:7018–27.

    Article  PubMed  CAS  Google Scholar 

  211. Khan MA, Van Dyk J, Yeung IW, Hill RP. Partial volume rat lung irradiation; assessment of early DNA damage in different lung regions and effect of radical scavengers. Radiother Oncol. 2003;66:95–102.

    Article  PubMed  Google Scholar 

  212. Van der Meeren A, Monti P, Vandamme M, Squiban C, Wysocki J, Griffiths N. Abdominal radiation exposure elicits inflammatory responses and abscopal effects in the lungs of mice. Radiat Res. 2005;163:144–52.

    Article  PubMed  Google Scholar 

  213. Leonard JM, Ye H, Wetmore C, Karnitz LM. Sonic Hedgehog signaling impairs ionizing radiation-induced checkpoint activation and induces genomic instability. J Cell Biol. 2008;183:385–91.

    Article  PubMed  CAS  Google Scholar 

  214. Emerit I, Quastel M, Goldsmith J, Merkin L, Levy A, Cernjavski L, et al. Clastogenic factors in the plasma of children exposed at Chernobyl. Mutat Res. 1997;373:47–54.

    Article  PubMed  CAS  Google Scholar 

  215. Pant GS, Kamada N. Chromosome aberrations in normal leukocytes induced by the plasma of exposed individuals. Hiroshima J Med Sci. 1977;26:149–54.

    PubMed  CAS  Google Scholar 

  216. Diallo I, Haddy N, Adjadj E, Samand A, Quiniou E, Chavaudra J, et al. Frequency distribution of second solid cancer locations in relation to the irradiated volume among 115 patients treated for childhood cancer. Int J Radiat Oncol Biol Phys. 2009;74:876–83.

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

Grant CA049062 from the National Institutes of Health supported research in the authors’ laboratories.

Author information

Authors and Affiliations

  1. Department of Radiology, New Jersey Medical School Cancer Center, University of Medicine and Dentistry of New Jersey, Newark, NJ, 07103, USA

    Edouard I. Azzam & Sonia M. de Toledo

  2. Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, 07103, USA

    Andrew L. Harris

  3. Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA

    Vladimir Ivanov, Hongning Zhou, Sally A. Amundson, Howard B. Lieberman & Tom K. Hei

Authors
  1. Edouard I. Azzam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sonia M. de Toledo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew L. Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vladimir Ivanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hongning Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sally A. Amundson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Howard B. Lieberman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tom K. Hei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edouard I. Azzam .

Editor information

Editors and Affiliations

  1. Brigham and Women’s Hospital, Francis Street 75, Boston, 01778, Massachusetts, USA

    Stephen T. Sonis

  2. Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, South Australia, Australia

    Dorothy M. Keefe

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Azzam, E.I. et al. (2013). The Ionizing Radiation-Induced Bystander Effect: Evidence, Mechanism, and Significance. In: Sonis, S., Keefe, D. (eds) Pathobiology of Cancer Regimen-Related Toxicities. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5438-0_3

Download citation

Publish with us

Policies and ethics

Search

Navigation